Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly. The etiology of AMD is complex and appears to involve both a genetic and an environmental component. The specific cause(s) of AMD are not known. Advancing age is perhaps the most important risk factor. Thus it is essential to understand how age-related changes in the retina, retinal pigment epithelium (RPE) and Bruch's membrane predispose some individuals to subsequent development of AMD. Several cellular pathways are likely involved in the pathobiology of AMD. Two pathways that have specifically been suggested to play a role in AMD pathogenesis are: oxidative stress and lipid/cholesterol metabolism. The goal of this proposal is to identify candidate genes and examine their contribution to AMD susceptibility. The hypotheses of this study are a) aging of the retina and the RPE is characterized by changes in gene expression, and b) genes whose expression levels are altered during aging may include genes that specifically contribute to AMD susceptibility. The specific aims are: 1) To examine gene expression profiles in human retina and RPE during aging. Expression profiles will be compared between young adults and elderly controls. In particular, age-related changes in expression of genes involved in response to oxidative stress and lipid/cholesterol metabolism will be analyzed. 2) To identify candidate genes and examine their contribution to AMD. Associations between AMD susceptibility and genes, whose expression levels were found to change consistently during aging, will be explored in 641 AMD patients and 112 controls.